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Title: Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists: Structure-Activity Effects.

Authors: Park, Hyejin; Jin, Un-Ho; Karki, Keshav; Allred, Clinton; Davidson, Laurie A; Chapkin, Robert S; Orr, Asuka A; Nowshad, Farrhin; Jayaraman, Arul; Tamamis, Phanourios; Safe, Stephen

Published In Toxicol Sci, (2021 Feb 26)

Abstract: Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2'-dihydroxy substituents and this included 2,2'-dihydroxy-, 2,2',4'-trihydroxy-, and 2,2',5'-trihydroxychalcones. In contrast, 2',4,5'-, 2'3',4'-, 2',4,4'-trihydroxy, and 2',3-, 2',4-, 2',4'-, and 2',5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2'-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.

PubMed ID: 33263770 Exiting the NIEHS site

MeSH Terms: Animals; Caco-2 Cells; Chalcones*/toxicity; Cytochrome P-450 CYP1A1/genetics; Cytochrome P-450 CYP1A1/metabolism; Cytochrome P-450 CYP1B1/genetics; Cytochrome P-450 CYP1B1/metabolism; Humans; Mice; Polychlorinated Dibenzodioxins*; Protein Binding; Receptors, Aryl Hydrocarbon/genetics; Receptors, Aryl Hydrocarbon/metabolism

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